Organ transplants require viable organs. For example, a successful kidney transplant requires a viable kidney. Currently, the number of patients waiting for kidneys far exceeds the number of kidneys available for donation. Similar conditions exist for other organs. Thus, attempts have been made to expand the donor pool for kidneys. For example, in addition to healthy volunteers (e.g., twin brother), kidneys may be harvested from brain-dead donors and even from heart-dead donors. Unfortunately, conventionally, there has been no objective, quantitative, non-invasive method to determine whether a kidney is viable. Visual observation of a kidney while being perfused is purely subjective and thus sub-optimal. Microdialysis and other invasive approaches can alter local tissue hemodynamics and metabolism and lead to unreliable and/or undesirable results. One conventional viability test involved performing a harvest-time biopsy. Unfortunately, in addition to being invasive and damaging cells, the biopsy may lead to potentially misleading results. For example, a biopsy may incorrectly report that a kidney is not viable because data may be acquired from cells damaged by the biopsy. Additionally, a kidney may be identified as being viable by the biopsy but then incur additional ischemic damage during transport that makes the kidney become non-viable. Therefore, there is a long felt and unmet need for objective, quantitative organ viability measurements acquired using a non-invasive approach that can be made in a transport/transplant relevant time frame.
The following defines acronyms that will be used throughout this application:    ATP adenosine triphosphate    ADP adenosine diphosphate    CSI chemical shift imaging    CSS cold static storage    HPP hypothermic pulsative perfusion    MR magnetic resonance    MRI magnetic resonance imaging    MRS magnetic resonance spectroscopy    NHBD non-heart beating donors    NMR nuclear magnetic resonance    Pi inorganic phosphorous    PME phosphomonoesther    PRESS point resolved spectroscopy    RF radio frequency    T Tesla
As early as 1990, papers like that by Boska, et al., Image Guided 31P Magnetic Resonance Spectroscopy (MRS) of Normal and Transplanted Human Kidneys, Kidney International, Vol. 38 (1990), pp 294-300, have reported that image guided 31P MRS of kidneys is possible. Boska described measuring and analyzing ratios like PME/ATP and Pi/ATP from data acquired during an hour long acquisition in a 2 T system using a spatially localized technique to obtain 31P MR kidney spectra in vivo and in situ.
In 2004, Niekisch et al., reported in Improved Pretransplant Assessment of Renal Quality By Means of Phosphorus-31 Magnetic Resonance Spectroscopy Using Chemical Shift Imaging, Transplantation, Vol. 77, 1041-1045, No. 7, Apr. 15, 2004, that 31P MRS can indicate graft quality by analyzing the ratio of PME to Pi in kidney. Niekisch describes a volume selective 31P-MRS using CSI. CSI was performed in a 2 T system using a standard PRESS sequence. Niekisch describes using two coils. A double tuned quadrature birdcage coil was used for RF excitation at both the 1H and 31P frequencies. The same coil was used for 1H imaging. A separate 31P actively decoupled loop coil was used to receive the 31P spectra signal from which the peaks were isolated. With the peaks isolated, the ratios could be computed. PME/Pi was calculated as an average PME/Pi value of all voxels containing the two metabolites. Niekish even cited back to an “early 80s study” by Chan et al., Studies of Human Kidneys Prior to Transplantation by Phosphorous NMR, in PEGG, et al., editors, Organ Preservation For Transplantation, New York, MTP Press, 1981, that described 31P spectroscopy of kidneys.
Thus, for at least two decades, scientists have researched 31P MRS for kidneys. However, none of this research has lead to a surgically relevant test for viability that can be performed in a timely manner in the multiplicity of locations where kidneys are harvested and transplanted. Therefore, non-viable kidneys continue to be transported and even, in some cases, transplanted. Similar research and issues exist for other organs.
Simply harvesting more kidneys would not solve the kidney transplant issue because once a kidney is harvested, it must be transported. While we are all familiar with the television portrayal of kidneys being transplanted in a cooler full of ice, the reality of 2010 is much different.
The reality of 2010 includes HPP machines like those described in 2007 in Buchs, et al., Interactive Cardio Vascular and Thoracic Surgery 6 (2007) 421-424, DO1:10.1510/icvts.2006.146043. Buchs describes an HPP machine for kidney perfusion that is also suitable for 31P NMR spectroscopy in a conventional MRI bore. Buchs describes computing the ratio of PME/Pi obtained from 31P spectroscopy where “31P NMR spectroscopy will be realized in a classical MRI apparatus transformed for the tests with a specific P-coil”. The Buchs apparatus includes three parts: an igloo, a drive module, and an umbilical cord. The “igloo” is a chamber that holds the kidney to be perfused. The chamber includes a disposable part, has a maximum size of 40 cm, and is suited for being placed in the bore of a conventional MRI apparatus. The maximum size is limited by the inner dimensions of the bore in the conventional MRI apparatus. The drive module provides positive O2 pressure and is not suited for placement in the bore of a conventional MRI apparatus. Thus, the umbilical cord, which is described as being 7 m long, connects the chamber to the drive module so that the chamber can be placed in the bore of an MRI apparatus while the drive module can be placed farther away from the bore where it will not be damaged by or damage the conventional MRI apparatus.
In 2010, Buchs reported even more recent data concerning 31P MRS in Buchs, et al., MRS for Organ Viability, Perfusion, (2010), DO1:10.1177/0267659110387184. Buchs reported that it is experimentally possible to evaluate the viability of organs during their re-perfusion after harvest by measuring ATP resynthesis using 31P MRS. Buchs relies on the fact that “the main marker of mitochondrial dysfunction is ATP depletion, which leads to apoptosis by activation of proaptic capsase enzymes.” Once again Buchs relies on a multi-part apparatus that includes a chamber, an umbilical cord, and a drive unit. This conventional system includes a chamber with a maximum size of 45 cm that is configured to fit in the bore of a conventional MRI apparatus. This conventional system also includes the support unit, which is connected to the chamber by a long umbilical cord so that it can sit “outside the Faraday Cage of the room the bore is in.” This conventional apparatus uses a “home made surface P-coil placed on the bottom of the chamber” to facilitate conducting phosphorous on a resonance at a frequency of 49.9 MHz in a 3 T B0 field.
Thus, NMR spectroscopy can provide information upon which a kidney viability decision can be made. NMR spectroscopy depends upon the fact that when placed in a magnetic field, NMR active nuclei (e.g., 1H, 31P) absorb at a frequency characteristic of the isotope. The resonant frequency, energy of the absorption, and the intensity of the signal are proportional to the strength of the magnetic field. NMR spectroscopy can also provide information on which the viability of other organs can be analyzed.
Depending on the local chemical environment, different protons in a molecule resonate at slightly different frequencies. Since both this frequency shift and the fundamental resonant frequency are directly proportional to the strength of the magnetic field, the shift is converted into a field-independent dimensionless value known as the chemical shift. The chemical shift is reported as a relative measure from some reference resonance frequency. This difference between the frequency of the signal and the frequency of the reference is divided by frequency of the reference signal to give the chemical shift. Frequency shifts may be extremely small in comparison to the fundamental NMR frequency. For example, a frequency shift might be only 100 Hz compared to a fundamental NMR frequency of 100 MHz. Thus, the chemical shift is generally expressed in parts per million (ppm). The chemical shift can be used to obtain some structural information about the molecule in a sample. The shape and size of peaks are indicators of chemical structure. FIG. 1 illustrates one example output from a chemical shift MRS of a kidney. Peaks are visible for PME, Pi, αATP, and βATP. The papers discussed in the background described how these peaks can be used to evaluate kidney viability. Chemical-shift MRI of other organs using other nuclei provides other information concerning organ viability.